rs7698598

Positions:

• chr4-119030492-A-G
• chr4-119030492-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133477.3(SYNPO2):​c.1717A>G​(p.Thr573Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.859 in 1,613,934 control chromosomes in the GnomAD database, including 596,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.85 (55271 hom., cov: 30)
  • Exomes 𝑓: 0.86 (541012 hom.)
• Consequence: SYNPO2 NM_133477.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.488

Genes affected

SYNPO2 (HGNC:17732): (synaptopodin 2) Enables alpha-actinin binding activity and filamin binding activity. Involved in positive regulation of actin filament bundle assembly; positive regulation of cell migration; and regulation of Rho-dependent protein serine/threonine kinase activity. Located in several cellular components, including Z disc; focal adhesion; and stress fiber. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.2677783E-7).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNPO2	NM_133477.3	c.1717A>G	p.Thr573Ala	missense_variant	4/5	ENST00000307142.9	NP_597734.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNPO2	ENST00000307142.9	c.1717A>G	p.Thr573Ala	missense_variant	4/5	1	NM_133477.3	ENSP00000306015	P1

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129464 AN: 151940 Hom.: 55223 Cov.: 30

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.879

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.805

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.868

Gnomad OTH AF: 0.877

GnomAD3 exomes AF: 0.853 AC: 214250 AN: 251162 Hom.: 91656 AF XY: 0.851 AC XY: 115551 AN XY: 135746

Gnomad AFR exome AF: 0.818

Gnomad AMR exome AF: 0.871

Gnomad ASJ exome AF: 0.886

Gnomad EAS exome AF: 0.878

Gnomad SAS exome AF: 0.800

Gnomad FIN exome AF: 0.816

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.863

GnomAD4 exome AF: 0.860 AC: 1256920 AN: 1461876 Hom.: 541012 Cov.: 88 AF XY: 0.858 AC XY: 623903 AN XY: 727232

Gnomad4 AFR exome AF: 0.822

Gnomad4 AMR exome AF: 0.874

Gnomad4 ASJ exome AF: 0.886

Gnomad4 EAS exome AF: 0.847

Gnomad4 SAS exome AF: 0.798

Gnomad4 FIN exome AF: 0.818

Gnomad4 NFE exome AF: 0.867

Gnomad4 OTH exome AF: 0.866

GnomAD4 genome AF: 0.852 AC: 129573 AN: 152058 Hom.: 55271 Cov.: 30 AF XY: 0.850 AC XY: 63177 AN XY: 74322

Gnomad4 AFR AF: 0.822

Gnomad4 AMR AF: 0.891

Gnomad4 ASJ AF: 0.879

Gnomad4 EAS AF: 0.868

Gnomad4 SAS AF: 0.808

Gnomad4 FIN AF: 0.805

Gnomad4 NFE AF: 0.868

Gnomad4 OTH AF: 0.878

Alfa AF: 0.870 Hom.: 118003

Bravo AF: 0.859

TwinsUK AF: 0.860 AC: 3190

ALSPAC AF: 0.869 AC: 3348

ESP6500AA AF: 0.820 AC: 3614

ESP6500EA AF: 0.870 AC: 7478

ExAC AF: 0.848 AC: 103006

Asia WGS AF: 0.865 AC: 3011 AN: 3478

EpiCase AF: 0.877

EpiControl AF: 0.871

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.76
DANN	Benign	0.13
DEOGEN2	Benign	0.0052	.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.027	T;T;T;T
MetaRNN	Benign	9.3e-7	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	.;N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.37	.;N;N;N
REVEL	Benign	0.068
Sift	Benign	1.0	.;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.022
MPC		0.076
ClinPred		0.0034	T
GERP RS		1.9
Varity_R		0.032
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7698598; hg19: chr4-119951647;